The long-term objective of this research is to understand the normal physiological function of IL-2 in brain, and to determine the role of this prototypic cytokine in pathophysiological processes of CNS. New theories and recent empirical data indicate that IL-2 may be involved in the pathogenesis of HIV-induced cognitive and neurobehavioral syndromes as well as other significant neuropsychiatric disorders (e.g., multiple sclerosis, Gullain-Barre syndrome, Alzheimer's disease, schizophrenia). This important immunoregulatory cytokine may also be pivotal in regulating other brain cytokines (e.g., IL-1, IL-6, TNF alpha) implicated in the pathophysiology of neuropsychiatric conditions such as HIV. Compelling evidence shows that IL-2 exerts prominent effects in the brains of animals and humans (e.g., cognitive, behavioral, neurochemical, neurotoxic), and appears to function as a neuromodulator. However, IL-2's fundamental site of action in brain, the IL-2 receptor (IL-2R) complex, is poorly understood. To this end, the laboratory of the P.I. was the first to clone and sequence cDNAs for subunits of the IL-2 receptor complex in brain, and assess the gene expression of these subunits by in situ hybridization histochemistry and ribonuclease protection methods. We have recently cloned a partial cDNA for the extracellular domain of the IL-2 beta (a subunit of the lymphocyte heterotimer complex which is known to be essential for intracellular signal transduction) and detected IL-2 beta message by in situ hybridization in the murine hippocampus. In addition, we recently cloned and sequenced a CDNA comprising the full length coding region of the IL-2R alpha accessory subunit from brain, and a partial brain IL-2R gamma cDNA. To determine the mechanism of action of IL-2 at the receptor level in the mammalian brain, the proposed studies will use molecular and pharmacological techniques to test the hypotheses: 1) that the subunits of the IL-2 receptor complex expressed by brain cells and lymphocytes are derived from the same gene coding sequences; 2) that there are subtypes of brain IL-2 receptors which are formed via differential expression of three distinct subunits (alpha, beta, and gamma); 3) that brain IL-2 receptor subtypes are localized to discrete anatomical regions, and; 4) that IL-2 receptors are expressed by neurons. In order to achieve the long-term objective of investigating systematically the physiological and pathophysiological effects of IL-2 in the CNS, the proposed studies are critical to establishing the fundamental molecular pharmacology and anatomy of brain IL-2 receptors. Successful completion of the proposed Specific Aims will then permit the testing of important hypotheses about the role of brain IL-2 receptors in pathophysiological processes relevant to HIV infection and multiple sclerosis (e.g., dysregulated CNS homeostatic and immune processes), schizophrenia (e.g., altered neurodevelopment), and Alzheimer's disease (e.g., neuronal degeneration).